Minimal effective concentration values of propafenone and 5-hydroxy-propafenone in acute and chronic therapy.
We evaluated the antiarrhythmic efficacy and the minimal effective concentrations of propafenone and its metabolite 5-hydroxy-propafenone during a) acute intravenous infusion (1.5 mg/kg in bolus followed by 45 minutes infusion), b) an acute oral single-dose test (450 mg), and c) 14-day chronic therapy (300 mg tid) followed by a washout. Oxidative metabolism was assessed by a debrisoquine oral test in every patient. Eleven patients with stable ventricular premature beats (VPBs) greater than or equal to 300/hr and Lown class greater than or equal to 3 completed the study. The main results emphasized a certain discrepancy between the clinical effect of the acute intravenous infusion (efficacy in 5 out of 11 patients) and of the acute oral test and chronic therapy (efficacy in 11/11), with a time lag of the ECG changes during the acute intravenous infusion. The minimal effective concentrations were lower after acute oral administration compared with chronic treatment both for propafenone (200 +/- 189 ng/ml vs. 492 +/- 530 ng/ml; p less than 0.05) and for 5-hydroxy-propafenone (82 +/- 40 ng/ml vs. 149 +/- 80 ng/ml; p less than 0.02). A linear correlation was demonstrated between drug/metabolite ratios of propafenone and debrisoquine, either after acute oral (r = 0.91) or after chronic administration (r = 0.84). The pharmacokinetics of propafenone was nonlinear and showed wide interindividual variations.(ABSTRACT TRUNCATED AT 250 WORDS)
Capucci
A
A
Institute of Cardiovascular Diseases, University of Bologna, Italy.
Boriani
G
G
Marchesini
B
B
Strocchi
E
E
Tomasi
L
L
Balducelli
M
M
Frabetti
L
L
Ambrosioni
E
E
Magnani
B
B
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D003647:Debrisoquin / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011405:Propafenone / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D013997:Time Factors
D011405:Propafenone; C044307:5-hydroxypropafenone; D003647:Debrisoquin